Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction

See allHide authors and affiliations

Science  25 May 2018:
Vol. 360, Issue 6391, pp. 888-893
DOI: 10.1126/science.aar6117

Reduction can make cobalt act precious

Enzymes rely on abundant metals such as iron and nickel to manipulate hydrogen. Chemists, on the other hand, have largely had to rely on precious metals such as platinum and rhodium for the task. Friedfeld et al. now report a simple trick to make cobalt act more like rhodium. Reduction of Co(II) to Co(I) by zinc reinforced binding of phosphine ligands to the metal to facilitate its use in asymmetric hydrogenation of alkenes. The cobalt catalysts tolerated alcohol solvents, unlike their rhodium congeners, and could be applied to a 200-gram-scale reduction at 0.08% loading.

Science, this issue p. 888


Identifying catalyst activation modes that exploit one-electron chemistry and overcome associated deactivation pathways will be transformative for developing first-row transition metal catalysts with performance equal or, ideally, superior to precious metals. Here we describe a zinc-activation method compatible with high-throughput reaction discovery that identified scores of cobalt-phosphine combinations for the asymmetric hydrogenation of functionalized alkenes. An optimized catalyst prepared from (R,R)-Ph-BPE {Ph-BPE, 1,2-bis[(2R,5R)-2,5-diphenylphospholano]ethane} and cobalt chloride [CoCl2·6H2O] exhibited high activity and enantioselectivity in protic media and enabled the asymmetric synthesis of the epilepsy medication levetiracetam at 200-gram scale with 0.08 mole % catalyst loading. Stoichiometric studies established that the cobalt (II) catalyst precursor (R,R)-Ph-BPECoCl2 underwent ligand displacement by methanol, and zinc promoted facile one-electron reduction to cobalt (I), which more stably bound the phosphine.

View Full Text